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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors
Chunhua Lu1, Corey Speers, Yun Zhang
1Department of Medicine, Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Background:
Although antiestrogens have been effective in preventing estrogen receptor (ER)-positive breast cancer, chemopreventive agents are still needed to prevent ER-negative breast cancer. Tyrosine kinase inhibitors are promising agents for the treatment and prevention of human cancers. ZD1839 (gefitinib or Iressa) is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways in epithelial cells. We examined whether ZD1839 blocks signal transduction and prevents the development of ER-negative breast cancer.
Methods:
The ability of ZD1839 to block signal transduction in normal, immortalized, and malignant breast cells was assessed by western blotting with specific antibodies to detect phosphorylation of cytoplasmic signaling molecules. The effect of ZD1839 on growth of these breast cells was assessed with anchorage-dependent and anchorage-independent growth assays. Its effect on ER-negative mammary tumorigenesis was assessed in MMTV-erbB2 transgenic mice. All statistical tests were two-sided.
Results:
ZD1839 suppressed the phosphorylation of EGFR and mitogen-activated protein kinase in normal and malignant breast cells. ZD1839 treatment statistically significantly suppressed mammary tumorigenesis in MMTV-erbB2 transgenic mice; median time to tumor development was approximately 230 days in vehicle-treated mice and more than 310 days in mice treated with ZD1839 at 100 mg/kg (P<.001). ZD1839 reduced proliferation of normal breast cells by 20.3% (95% confidence interval [CI] = -13.7% to 44.2%) and of tumor cells by 42.0% (95% CI = 20.2% to 58.2%). ZD1839 also increased expression of the cell cycle regulator p27 in normal mammary tissue by 48.7% (95% CI = 27.0% to 74.2%) and in tumor tissue by 50.3% (95% CI = 35.8% to 66.7%).
Conclusion:
This study appears to provide the preclinical rationale for the development of these EGFR tyrosine kinase inhibitors for the prevention of human breast cancer.
Insights
ZD1839, an EGFR tyrosine kinase inhibitor, effectively suppressed ER-negative breast cancer development in mice by blocking key signaling pathways. This research supports its potential as a novel chemopreventive agent for breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Prevention
Background:
- Estrogen receptor (ER)-positive breast cancer is treatable with antiestrogens, but ER-negative breast cancer lacks effective chemopreventive agents.
- Tyrosine kinase inhibitors (TKIs) show promise for cancer treatment and prevention.
- ZD1839 (gefitinib) is an orally active epidermal growth factor receptor (EGFR) TKI that inhibits signal transduction.
Purpose of the Study:
- To investigate if ZD1839 can block signal transduction pathways.
- To determine the efficacy of ZD1839 in preventing ER-negative breast cancer development.
Main Methods:
- Western blotting was used to assess ZD1839's effect on signal transduction in breast cells.
- Growth assays evaluated ZD1839's impact on breast cell proliferation.
- MMTV-erbB2 transgenic mice were used to assess ZD1839's effect on mammary tumorigenesis.
Main Results:
- ZD1839 suppressed EGFR and mitogen-activated protein kinase phosphorylation in breast cells.
- Mammary tumorigenesis was significantly suppressed in ZD1839-treated mice (median time >310 days vs. ~230 days).
- ZD1839 reduced normal breast cell proliferation by 20.3% and tumor cell proliferation by 42.0%, while increasing p27 expression.
Conclusions:
- ZD1839 effectively blocks EGFR signaling pathways.
- This study provides preclinical evidence for developing EGFR TKIs like ZD1839 for breast cancer prevention.
